Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice
Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice
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DOI：
10.1172/jci34827
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发表时间：
2008-09-01
影响因子：
15.9
通讯作者：
Kunos, George
中科院分区：
文献类型：
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作者：
Osei-Hyiaman, Douglas;Liu, Jie;Kunos, George
饮食诱导的肥胖与脂肪肝、胰岛素抵抗、瘦素抵抗和血脂变化有关。内源性大麻素与这些相关表型的发展有关，因为缺乏大麻素受体CB的小鼠(CB1(-/-))不会表现出与饮食诱导的肥胖相关的这些变化。然而，介导这些效应的靶组织仍不清楚。因此，我们使用肝脏特异性CBI基因敲除(LCB1(-/-))小鼠，研究了肝脏和肝外CBI受体在高脂饮食的代谢后果中的相对作用。喂食高脂饮食的LCB1(-/-)小鼠的肥胖程度与野生型小鼠相似，但与喂食高脂饮食的野生型小鼠相比，LCB1(-/-)小鼠的脂肪变性、高血糖、血脂异常以及胰岛素和瘦素抵抗较少。CB1(-/-)和LCB1(-/-)小鼠未见CB1(-/-)和LCB1(-/-)小鼠肝脏脂肪生成增加，肉碱氨基转移酶-1活性和总能量消耗降低。我们的结论是，肝脏CB受体的内源性大麻素激活有助于饮食诱导的脂肪变性和相关的激素和代谢变化，而不是高脂饮食下观察到的肥胖症的增加。这些研究表明，在肥胖相关疾病的治疗过程中，外周血CBI受体可以选择性地靶向治疗脂肪肝、糖稳态受损和血脂异常，以最大限度地减少非选择性CB受体的神经精神副作用。
Diet-induced obesity is associated with fatty liver, insulin resistance, leptin resistance, and changes in plasma lipid profile. Endocannabinoids have been implicated in the development of these associated phenotypes, because mice deficient for the cannabinoid receptor CB, (CB1(-/-)) do not display these changes in association with diet-induced obesity. The target tissues that mediate these effects, however, remain unknown. We therefore investigated the relative role of hepatic versus extrahepatic CBI receptors in the metabolic consequences of a high-fat diet, using liver-specific CBI knockout (LCB1(-/-)) mice. LCB1(-/-) mice fed a high-fat diet developed a similar degree of obesity as that of wild-type mice, but, similar to CB1(-/-) mice, had less steatosis, hyperglycemia, dyslipidemia, and insulin and leptin resistance than did wild-type mice fed a high-fat diet. CBI agonist-induced increase in de novo hepatic lipogenesis and decrease in the activity of carnitine paimitoyltransferase-1 and total energy expenditure were absent in both CB1(-/-) and LCB1(-/-) mice. We conclude that endocannabinoid activation of hepatic CB, receptors contributes to the diet-induced steatosis and associated hormonal and metabolic changes, but not to the increase in adiposity, observed with high-fat diet feeding. Theses studies suggest that peripheral CBI receptors could be selectively targeted for the treatment of fatty liver, impaired glucose homeostasis, and dyslipidemia in order to minimize the neuropsychiatric side effects of nonselective CB, blockade during treatment of obesity-associated conditions.